Ethynylbenzene compounds and derivatives thereof to treat inflammation, pain or fever

ABSTRACT

A method of treating patients by administering an effective amount of a compound which is a hydroxy, alkoxy or acyloxy ethynylbenzene, and the pharmaceutical preparation thereof.

This is a division, of application Ser. No. 574,837, filed May 14, 1975.Application Ser. No. 574,837 is a continuation of Application Ser. No.431,254, filed Jan. 7, 1974, now U.S. Pat. No. 3,923,910 which is adivision of Application Ser. No. 268,419, filed July 3, 1972, now U.S.Pat. No. 3,852,364.

SUMMARY OF THE INVENTION

This invention describes novel ethynylbenzene compounds and derivativesand their use in therapeutic compositions. In addition, this inventiondescribes the preparation of these ethynylbenzene compounds and theirderivatives. When the compounds of this invention are administered tomammals, they afford significant treatment for the relief ofinflammation and associated pain and fever.

They further provide analgesic and antipyretic methods for the reliefand treatment of pain and fever.

BACKGROUND OF THE INVENTION

Continued studies have been carried out during the last decade todevelop drugs which would significantly inhibit the development ofinflammation and relieve pain and fever as well as the pain and feverassociated with inflammation. While much of this effort has been carriedout in the steroid field, there have been compounds developed which arenon-steroidal but all of this type are acidic in nature, e,g.,arylalkanoic acids, heterylalkanoic acids, pyrazolidinedions. While manyof these compounds have been found to be effective, they have had thedrawback of causing various side effects, in particular, gastrichemorrhage and ulceration.

I have unexpectedly found that ethynylbenzene compounds havepharmacological properties which are useful for the relief andinhibition of inflammation conditions and are neutral substances.

I have also found that the compounds of this invention are effective inthe treatment of inflammation and the control of arthritic conditionsassociated with inflammation, without producing gastric hemorrhage orulceration commonly associated with anti-inflammatory agents.

I have further found that the ethynylbenzene compounds and derivativesof this invention are novel.

I have also found that the compounds of this invention possess usefulanalgesic and antipyretic properties and are useful in the treatment ofpain and fever.

I have still further found an entirely new class of antiinflammatory,analgesic and antipyretic pharmaceutical compositions which contain anethynylbenzene compound derivative thereof as active ingredient.

I have also found a convenient method for synthesizing these compounds.

DESCRIPTION AND PREFERRED EMBODIMENTS

This invention comprises a class of novel chemical compounds which areethynylbenzene compounds or derivatives. Also the benzene ring isfurther substituted.

This invention also describes a new method for treating inflammation aswell as pain and fever and also novel therapeutic compositions.

The compounds of this invention can be represented by the genericstructure which is described by the general formula I; ##STR1## where Ris alkyl,

cycloalkyl,

alkylcycloalkyl,

cycloalkenyl,

aryl or

substituted aryl where the substituent is Y";

Y' and Y" are hydrogen,

alkyl,

halo,

nitro,

amino,

acylamino,

mono and diloweralkylamino,

mercapto,

acylthio,

loweralkylthio,

loweralkylsulfinyl,

loweralkylsulfonyl,

hydroxy,

loweralkoxy,

acyloxy,

haloloweralkyl,

cyano or

acetyl;

with the proviso that when R is phenyl then at least one of Y' and Y"are other than hydrogen.

The para position is the preferred position for the R substituents.

The meta position is the preferred position for the Y and Y'substituents, and the ortho position is the preferred position for theY" substituents.

More specifically, the chemical compounds of this invention which haveparticular usefulness as antiinflammatory, analgesic and antipyreticagents, such antiinflammatory activity being enjoyed as a result ofinhibition of blood platelet aggregation, with associatedanti-thrombotic effects in vascular thrombosis, and whose properties aredescribed by formulae II-IV: ##STR2## where Alk is alkyl having 3-7carbon atoms. ##STR3## where x is 0-2. ##STR4##

Those compounds whose properties are even more preferred are describedby formulae II-III where

Y is hydrogen,

halo,

nitro, cyano,

loweralkylsulfonyl or

haloloweralkyl; and

x=1.

The more preferred compounds of formula IV are those where Y is halo.

Compounds which are most preferred are those where Y is halo and chlorois particularly preferred.

In the descriptive portions of this invention the following definitionsapply:

"Alkyl" refers to a loweralkyl hydrocarbon group containing from 1 toabout 7 carbon atoms which may be straight chained or branched.

"Alkenyl" refers to an unsaturated or partially unsaturated hydrocarbongroup containing from 2 to about 7 carbon atoms which may be straightchained or branched.

"Cycloalkyl" refers to a hydrocarbon ring having up to about sevencarbon atoms.

"Cycloalkenyl" refers to a partially unsaturated hydrocarbon ring havingup to about seven carbon atoms.

"Aryl" refers to any benzenoid or non-benzenoid aromatic group butpreferably phenyl.

"Alkoxy" refers to a loweralkoxy group containing from 1 to about 6carbon atoms which may be straight chained or branched.

"Acyl" refers to any organic radical derived from an organic acid by theremoval of its hydroxyl group such as formyl, acetyl, propionyl.

It should also be realized by one skilled in the art that the followingcompounds may also be employed in the practice of this invention where

R is aryloxy,

arylthio,

arylamino,

aroyl or

heteryl.

The preferred "aroyl" is benzoyl, loweralkylbenzoyl such as toluoyl orhalobenzoyl such as p-chlorobenzoyl, etc.

"Heteryl" refers to a heterocyclic ring having 5-7 atoms which issaturated, partially saturated or unsaturated and containing one or moreof the same or different hetero atoms of N, S or O.

Representative heteryl rings include such as thienyl, furyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyranyl, 2H-pyrrolyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolinyl,piperidyl, piperazinyl, morpholinyl.

The compounds of this invention may be prepared by the following generalprocedure.

Condensation of a substituted benzene compound with a loweralkyl oraralkyl oxalyl chloride in the presence of anhydrous aluminum chlorideresults in a p-substitutedphenylglyoxylate. The loweralkyl or aralkylesters of the p-substitutedphenyl glyoxylic acid may be halogenated ornitrated to obtain the corresponding loweralkyl esters of a3-halo-4-substitutedphenylglyoxylic acid or a3-nitro-4-substitutedphenylglyoxylic acid. Chlorination or brominationmay be carried out in the presence of a small amount of iodine dissolvedin an inert solvent such as carbon tetrachloride. A solution of chlorineor bromine is then added while the temperature is held near 0° C.Nitration is carried out with fuming nitric acid at about 0° C. Thefollowing reaction equations illustrate this method. ##STR5## where R isas described above and Hal is chloro.

Appropriately desired end products having various Y and Y' substitutentscan be prepared by using suitable reactions in order to convert onegroup to another. Thus, for example, a3-halo-4-substitutedphenylglyoxylate in which halo is chloro, bromo oriodo may be

(a) reacted with cuprous cyanide in quinoline at about 150° C. toproduce a 3-cyano-4-substitutedphenylglyoxylate;

(b) reacted with trifluoromethyliodide and copper powder at about 150°C. in dimethylformamide to obtain a3-trifluoromethyl-4-substitutedphenylglyoxylate: [as described inTetrahedron Letters: 47, 4095 (1959)];

(c) reacted with cuprous methanesulfinate in quinoline at about 150° C.to obtain a 3-methylsulfonyl-4-substitutedphenylglyoxylate.

A 3-nitro-4-substitutedphenylglyoxylate may be selectively hydrogenatedto the corresponding amine.

A 3-amino-4-substitutedphenylglyoxylate may then be

(a) mono- or dialkylated with loweralkyl halides or sulfates or acylatedwith loweracyl chlorides or anhydrides;

(b) diazotized to the diazonium fluoroborate which is then thermallydecomposed to the 3-fluoro-4-substitutedphenylglyoxylate,

(c) diazotized and heated in an aqueous medium to form the3-hydroxy-4-substitutedphenylglyoxylate or heated in an alcohol to formthe 3-alkoxy-4-substitutedphenylglyoxylate. The hydroxyl group may alsobe alkylated with loweralkyl halides or sulfates to the alkoxyl group oracylated with loweracyl chlorides or anhydrides to the acyloxy compoundin the presence of a tertiary amine such as pyridine,

(d) diazotized followed by a Sandmeyer type reaction to yield the halogroup,

(e) diazotized and heated with an aqueous solution of potassium iodideto prepare the 3-iodo-4-substitutedphenylglyoxylate,

(f) diazotized and followed by addition of cuprous cyanide to obtain the3-cyano-4-substitutedphenylglyoxylate which in turn may be esterifiedwith an alcohol or hydrolyzed to the amide or carboxylic acid of theglyoxylic acid,

(g) diazotized followed by reaction with potassium ethylxanthatefollowed by hydrolysis to obtain 3-mercapto-4-substitutedphenylglyoxylicacid which can be esterified to a3-mercapto-4-substitutedphenylglyoxylate. This in turn can be loweralkylated to the lower alkylthio and oxidized to the loweralkylsulfinyland loweralkylsulfonyl groups or acylated to the acylthio compounds.

A second nitration or halogenation may be carried out on the3-substitutedglyoxylate to obtain the corresponding3,5-disubstitutedglyoxylate. This may be carried out at any appropriatestage of the synthesis in order to obtain the desired substituents.Thus, for example, a 3-chloro-4-substitutedphenylglyoxylate may benitrated as above to obtain a3-chloro-5-nitro-4-substitutedphenylglyoxylate or chlorinated to obtaina 3,5-dichloro-4-substitutedphenylglyoxylate. A3-nitro-4-substitutedphenylglyoxylate can be nitrated to give a3,5-dinitro-4-substitutedphenylglyoxylate.

Reduction of the glyoxylate ester is accomplished by lithium aluminumhydride to give the 1,2-ethanediol (a). When the 1,2-ethanediol istreated with periodic acid the corresponding aldehyde is prepared (b).Alternatively, the glyoxylate ester may be converted to the glyoxylicacid by acid hydrolysis, and the latter with heat decarboxylated to thesubstituted benzaldehyde. The latter method is used when Y or Y' aresubstituents sensitive to LiAlH₄ reduction, e.g., NO₂, SH, SR, SOR, I.

Claisen condensation of a substitutedbenzaldehyde with an acetic acidester (preferably a loweralkyl or benzyl ester) in the presence of ametal alkoxide results in a β-substitutedphenylacrylic ester. Thealdehyde may also be subjected to a Perkin reaction with aceticanhydride and an acetic acid salt or through a Knoevenogel condensationusing malonic acid and ammonia in an amine base to obtainβ-substitutedphenylacylic acid (c). Addition to the double bond withhalogen (preferably bromine) results in an α,β-dibromopropionic acid orester (d). When the α,β-dibromopropionate is added to an alcoholicpotassium hydroxide solution and heated for several hours thecorresponding propiolic acid is prepared (e). Heating the propiolic acidat raised temperature in quinoline for 2-10 hours results in the desiredacetylene compound (f). ##STR6## where R, Y and Y' are as describedabove and R" is loweralkyl or butyl.

When Y and Y' substitution is desired in the ortho position of thephenyl ring then the halogenation and nitration may be carried out in asimilar manner but on the propiolic acid or ester or on the desiredacetylene.

A further preparation of the compounds of this invention may be carriedout starting with a substitutedacetophenone and reacting the ketofunction with a halogenating agent such as phosphorus pentachloride andphosphorus oxychloride and the like. The resultant dihalo compound isthen dehalogenated using sodamide in liquid ammonia to obtain thedesired acetylene. This is particularly useful in obtaining the3-halo-4-substitutedphenylacetylene from3-halo-4-substitutedacetophenone. ##STR7##

I have found that the compounds of this invention exercise a usefuldegree of anti-inflammatory activity in mammals and are effective in thetreatment of associated pain and fever and in like conditions includingthe inhibition of platelet aggregation in the blood, which inhibition iseffective in the prevention of thrombosis formation (i.e. vascularthrombosis) and other conditions inherently treated by inhibition ofblood platelet aggregation which are responsive to treatment withanti-inflammatory agents. In general, the compounds of this inventionare indicated for a wide variety of mammalian conditions where thesymptoms of inflammation and associated fever and pain are manifested.Exemplary of such conditions are: rheumatic diseases such as rheumatoidarthritis, osteoarthritis and other degenerative joint diseases;soft-tissue rheumatism such as tendinitis; muscular rheumatism such assciatica; pain and inflammation associated with dental surgery andsimilar human and veterinary disease conditions exhibiting the foregoingsymptoms requiring the use of an anti-inflammatory, analgesic and/orantipyretic agent.

I have also found that the compounds of this invention show a markeddegree of analgesic activity and are effective in the relief of pain andfever. These compounds are essentially devoid of gastric hemorrhage sideeffects.

For all the above purposes, the compounds of this invention are normallyadministered orally, topically, parenterally or rectally. Orally, thesemay be administered in tablets, capsules, suspensions or syrups; theoptimum dosage, of course, depending on the particular compound beingused and the type and severity of the condition being treated. In anyspecific case the appropriate dosage selected will further depend onfactors of the patient which may influence responses to the drug; forexample, general health, age, weight, etc. Although the optimumquantities of the compounds of this invention to be used in such mannerwill depend on the compound employed and the particular type of diseasecondition treated, oral dose levels of preferred compounds whenadministered to a mammal in dosages of 0.5 to 100 milligrams perkilogram of body weight per day are particularly useful. The preferredrange is 0.5 to 15 mg/kg. Comparative dosages may be used in topical,parenteral or rectal administration.

Dosage forms may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents; for example, sweetening agents,flavoring agents, coloring agents, preserving agent, etc. Further, theactive acetylenic compounds may be administered alone or in admixturewith antacids such as sodium bicarbonate, magnesium carbonate, magnesiumhydroxide, aluminum hydroxide, magnesium silicate, etcl, and non-toxicpharmaceutically acceptable excipients. Such excipients may be, forexample, inert diluents such as calcium carbonate, lactose, etc.,granulating and disintegrating agents; for example maize starch, alginicacid, etc., lubricating agents; for example, magnesium stearate, talc,etc., binding agents; for example, starch gelatin, etc., suspendingagents; for example, methylcellulose, vegetable oil, etc., dispersingagents; for example, lecithin, etc., thickening agents; for example,beeswax, hard paraffin, etc., emulsifying agents; for example,naturally-occurring gums, etc., and non-irritating excipients; forexample, cocoa butter and polyethylene glycols.

Various tests in animals can be carried out to show the ability of theacetylenic compounds of this invention to exhibit reactions that can becorrelated with anti-inflammatory activity in humans. One such test isthe carrageenan paw edema test, which shows the ability of the instantcompounds to inhibit edema induced by injection of an inflammatory agentsuch as carrageenan into the tissues of the paw of a rat againstnoninflammed controls. This carrageenan testing method is known tocorrelate well with anti-inflammatory activity in humans and is astandard test used to determine anti-inflammatory activity. Thiscorrelation can be shown by the activities of compounds known to beclinically active including such as aspirin, phenylbutazone, cortisone,hydrocortisone, indomethacin and prednisolone. In view of the results ofthis test, the acetylenic compounds of this invention can be consideredto be active anti-inflammatory agents.

A further test to show anti-inflammatory activity is the polyarthritistest in rats. This test is carried out on the animal model which closelyresembles human arthritis and is widely used in the art. This isoutlined by Winter & Nuss in Arthritis and Rheumatism 9: 394, (1966). Inview of the results of this test, the acetylenic compounds of thisinvention can be considered to be active anti-inflammatory agents.

One method for measuring analgesic activity is the acetic acid writhingtest as outlined by Siegmund et al in the Proc. Soc. Exp. Biol. Med. 95:729-731, (1957). This method involves the intraperitoneal injection of60 mg/kg of HOAc (0.6% solution; 0.1 ml/10 g) into male albino micewhich produces a syndrone characterized by stretching movement.Analgesics prevent or suppress the stretch.

In view of the results of this test, the acetylenic compounds of thisinvention are considered to demonstrate non-narcotic analgesic activity.

One method of measuring gastric hemorrhage is as follows.

Albino male rats weighing 100-120 g are fasted for 24 hours but givenfree access to water. The animals are placed in groups of 10 animals perdose and dosed by gastric gavage at a volume of 1 ml/100 g body weightwith test compound suspended in 0.5% methylcellulose. A control groupreceives only 0.5% methylcellulose. Four hours after administration ofcompound, the animals are sacrificed and the rumens of the stomachsassayed for gastric hemorrhage. Hemorrhage is defined as an area ofblood which is 1 mm or larger at the largest diameter. Diameter of thehemorrhage is recorded. The number of animals in each group withstomachs having at least one area of hemorrhage is recorded. Thepresence of areas of blood smaller than 1 mm, defined as petechiae, isnoted but not counted in the assay. The percent hemorrhage for eachgroup is statistically analyzed to determine the dose magnitude (ED₅₀)which causes production of gastric hemorrhage in 50% of the animals.

The following are detailed examples which show the preparation of thecompounds of this invention. They are to be construed as illustrationsof said compounds and are not intended to be limitations thereof.

EXAMPLE 1 Ethyl 4-cyclohexylphenylglyoxylate

Cyclohexylbenzene 53 g. (0.33 mole) and 50.5 g. (0.37 mole) of ethyloxalyl chloride are dissolved in 200 ml. of dry1,1,2,2-tetrachloroethane. Anhydrous aluminum chloride 52 g. (0.39 mole)is added in small portions to the reaction mixture with stirring over 2hours. During the addition, the temperature of the mixture is maintainedbetween 16°-18° C. The mixture is stirred for an additional hour andallowed to stand overnight. The solution is then slowly poured into 1500ml. of iced saline solution with stirring. After standing, two layersform. The aqueous layer is extracted with 500 ml. of ether and the etherextract is combined with the organic layer which is dissolved in 1500ml. of ether and separated. The ether solution is washed with 10×100 ml.portions of a 1:1 mixture of saturated sodium chloride solution and 10%HCl solution, and 5×100 ml. portions of water. The ether solution isthen dried over anhydrous magnesium sulfate for 1 hour and filtered. Thesolvents are removed by distillation under reduced pressure and theresidue distilled to obtain ethyl 4-cyclohexylphenylglyoxylate.

When cyclohexylbenzene in the above example is replaced withcyclopentylbenzene, cycloheptylbenzene, 2'-methylcyclohexylbenzene,biphenyl i-propylbenzene, i-butylbenzene, t-butylbenzene,cyclohex-1-enylbenzene, cyclohex-3-enylbenzene then the productsprepared are ethyl p-cyclopentylphenylglyoxylate, ethylp-cycloheptylphenylglyoxylate, ethylp-(2'-methylcyclohexyl)phenylglyoxylate, ethyl p-biphenylylglyoxylate,ethyl p-i-propylphenylglyoxylate, ethyl p-i-butylphenylglyoxylate, ethylp-t-butylphenylglyoxylate.

EXAMPLE 2 Ethyl 3-chloro-4-cyclohexylphenylglyoxylate

Ethyl p-cyclohexylphenylglyoxylate 98.9 g. (0.38 mole) and 6.1 g. ofiodine (0.048 mole) and dissolved in 100 ml. of carbon tetrachloride. Tothis solution is added a solution of 40.4 g. (0.57 mole) of chlorinedissolved in 365 ml. of carbon tetrachloride over a period of 2 hours.During the addition, the temperature of the reaction mixture ismaintained at 0° C. The mixture is stirred for 3 hours and allowed tostand with gradual warming to room temperature over 15 hours. Thesolvent is removed by distillation under reduced pressure. The residueis fractionally distilled to obtain ethyl3-chloro-4-cyclohexylphenylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedwith the esters of Example 1 then the corresponding product of Table Ibelow is prepared.

Table I

ethyl 3-chloro-4-cyclopentylphenylglyoxylate

ethyl 3-chloro-4-cycloheptylphenylglyoxylate

ethyl 3-chloro-4-(2'-methylcyclohexyl)phenylglyoxylate

ethyl 3-chloro-4-biphenylglyoxylate

ethyl 3-chloro-4-i-propylphenylglyoxylate

ethyl 3-chloro-4-i-butylphenylglyoxylate

ethyl 3-chloro-4-t-butylphenylglyoxylate

EXAMPLE 3 Ethyl 3,5-dichloro-4-cyclohexylphenylglyoxylate

Ethyl p-cyclohexylphenylglyoxylate, 49.5 g. (0.19 mole) and 6.1 g. ofiodine are dissolved in 100 ml. of carbon tetrachloride. To thissolution is added a solution of 56.7 g. (0.8 mole) of chlorine dissolvedin 500 ml. of carbon tetrachloride over a period of 3 hours. During theaddition, the temperature of the reaction mixture is maintained at 0° C.The mixture is stirred for 3 hours and allowed to stand with gradualwarming to room temperature over 30 hours. The solvent is removed invacuo. The residue is fractionally distilled to obtain ethyl3,5-dichloro-4-cyclohexylphenylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Example 1, then the corresponding product is prepared.

EXAMPLE 4

When bromine is used in place of chlorine in Example 2, the productsobtained are shown in Table I below.

Table I

ethyl 3-bromo-4-cyclopentylphenylglyoxylate

ethyl 3-bromo-4-cycloheptylphenylglyoxylate

ethyl 3-bromo-4-cyclohexylphenylglyoxylate

ethyl 3-bromo-4-(2'-methylcyclohexyl)phenylglyoxylate

ethyl 3-bromo-4-biphenylylglyoxylate

ethyl 3-bromo-4-i-propylphenylglyoxylate

ethyl 3-bromo-4-i-butylphenylglyoxylate

ethyl 3-bromo-4-t-butylphenylglyoxylate

When bromine is used in place of chlorine in Example 3, thecorresponding products are obtained.

EXAMPLE 5 Ethyl 3-nitro-4-cyclohexylphenylglyoxylate

Ethyl p-cyclohexylphenylglyoxylate 17.2 g. (0.066 mole) is added toice-cold concentrated sulfuric acid (18 ml) and stirred with cooling for5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml.) is addeddropwise, maintaining the temperature between 30° and 40° by watercooling if necessary. After addition of the nitric acid is complete, themixture is stirred for 1/2 hour, then poured into water. The mixture ismade alkaline with sodium hydroxide, then extracted with ether. Theether extract is washed, dried over sodium sulfate, evaporated and theresidue is fractionally distilled to obtain ethyl3-nitro-4-cyclohexylphenylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Example I, then the corresponding product of Table Ibelow is prepared.

Table I

ethyl 3-nitro-4-cyclopentylglyoxylate

ethyl 3-nitro-4-cycloheptylphenylglyoxylate

ethyl 3-nitro-4-(2'-methylcyclohexyl)phenylglyoxylate

ethyl 3-nitro-4-biphenylylglyoxylate

ethyl 3-nitro-4-i-propylphenylglyoxylate

ethyl 3-nitro-4-i-butylphenylglyoxylate

ethyl 3-nitro-4-t-butylphenylglyoxylate

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Examples 3 and 4, then the corresponding product isprepared.

EXAMPLE 6 Ethyl 3,5-dinitro-4-cyclohexylphenylglyoxylate

Ethyl p-cyclohexylphenylglyoxylate 17.2 g. (0.066 mole) is added toice-cold concentrated sulfuric acid (54 ml. ) and stirred with coolingfor 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (7.5 ml.) is addeddropwise, maintaining the temperature between 30° and 40° by watercooling if necessary. After addition of the nitric acid is complete, themixture is stirred for 3 hours, then poured into water. The mixture ismade alkaline with sodium hydroxide, then extracted with ether. Theether extract is washed, dried over sodium sulfite, evaporated and theresidue is fractionally distilled to obtain ethyl3,5-dinitro-4-cyclohexylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Example 1, then the corresponding product is prepared.

EXAMPLE 7 Ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate

To a solution of 0.01 moles of ethyl3-bromo-4-cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide isadded 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder.The reaction is shaken in a sealed tube for 5 hours at 140° C., cooled,and then filtered and evaporated in vacuo. 200 ml. of water is added tothe residue and extracted with ether. The ether extract is dried,evaporated to dryness and distilled to obtain ethyl3-trifluoromethyl-4-cyclohexylphenylglyoxylate.

When ethyl 3-bromo-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the appropriate compounds of Examples 4and 5, then the corresponding product is obtained.

EXAMPLE 8 Ethyl 3-amino-4-cyclohexylphenylglyoxylate

A mixture of 15.3 g. (0.05 moles) of ethyl3-nitro-4-cyclohexylphenylglyoxylate in 100 ml. methanol containing 0.05mole citric acid and 1.5 g. of 5% palladium-on-carbon is shaken withhydrogen at 3 atm. pressure and 27° C. until 3 moles of hydrogen areabsorbed. The mixture is filtered, washed with methanol and the filtrateconcentrated in vacuo to obtain ethyl3-amino-4-cyclohexylphenylglyoxylate, isolated as the citrate salt.

When ethyl 3-nitro-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the appropriate compounds of Exampls 5and 6, then the corresponding products are obtained.

EXAMPLE 9 Ethyl 3-methylamino-4-cyclohexylphenylglyoxylate

To a solution of 0.01 moles of ethyl3-amino-4-cyclohexylphenylglyoxylate in 100 ml. of pyridine is added 0.1moles of methyl iodide. The reaction mixture is stirred overnight atroom temperature, filtered and concentrated. The residue is distilled toobtain ethyl 3-methylamino-4-cyclohexylphenylglyoxylate.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the compounds of Example 8, then thecorresponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyl iodide inthe above example, then the product prepared isethyl-3-acetylamino-4-cyclohexylphenylglyoxylate.

EXAMPLE 10 Ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate

A solution of 0.005 moles of ethyl 3-nitro-4-cyclohexylphenylglyoxylateand 1.6 ml. of 37% formaldehyde in 50 ml. of methanol is shaken withhydrogen over 0.5 g. of 5% palladium-on-charcoal at 42 lbs. and 27° C.until five moles of hydrogen are absorbed. The catalyst is filtered offand the filtrate is evaporated in vacuo. The residue is then distilledto obtain ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate.

When ethyl 3-nitro-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the appropriate compounds of Examples 5and 6, then the corresponding products are obtained.

EXAMPLE 11 Ethyl 3-cyano-4-cyclohexylphenylglyoxylate

To 29.4 g. (0.1 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate in35 ml. of 28% hydrochloric acid and 100 ml. of cracked ice to maintainthe temperature at 0° C. is added a solution of 7.1 g. (0.102 moles) ofsodium nitrite in 20 ml. of water. The reaction mixture is thenneutralized with sodium carbonate. This diazonium mixture is added to acuprous cyanide solution (prepared from 31.5 g. of copper sulfate and16.2 g. of sodium cyanide in 75 ml. of water). 250 ml. of toluene isalso added and the mixture is stirred for 1/2 hour. The reaction is thenallowed to stir an additional 2 hours while warming gradually to 50° C.This is then cooled and the toluene separated, dried over sodium sulfateand evaporated to dryness to obtain ethyl3-cyano-4-cyclohexylphenylglyoxylate.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the compounds of Example 8, then thecorresponding products are obtained.

EXAMPLE 12 Ethyl 3-fluoro-4-cyclohexylphenylglyoxylate

To 44.2 g. (0.15 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate isadded at 0° C. 44 ml. of 1.5 moles of concentrated hydrochloric acid.The reaction mixture is maintained at 0° C. and the diazonium salt isprepared with 23.2 g. (0.32 moles) of 95% sodium nitrite in 80 ml. ofwater. To this mixture is rapidly added a solution of 10.4 g. (0.17moles) of boric acid dissolved in 22 g. (0.66 moles) of 60% hydrofluoricacid. The reaction mixture is then stirred for 1/2 hour and filtered,washed with 3×25 ml. of water, 2×25 ml. of methanol and 25 ml. of ether.The residual cake is then treated in vacuo. The treated cake is thenplaced in a distilling flask and heated to permit spontaneousdecomposition. After the decomposition, the residue is then fractionallydistilled to obtain ethyl 3-fluoro-4-cyclohexylphenylglyoxylate.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by the compounds of Example 8, then the corresponding productsare obtained.

EXAMPLE 13 3-Hydroxy-4-cyclohexylphenylglyoxylic acid

To 4.5 g. of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in125 ml. of 80% hydrochloric acid and cooled to 0° C. is added dropwise asolution of 1.2 g. of sodium nitrite in 15 ml. of water. After about 10min., 200 ml. of 50% hydrochloric acid is added portion wise and stirredfor 15 hours. The reaction mixture is then poured onto ice water andextracted with chloroform, dried over sodium sulfate and concentrated invacuo. The residue is crystallized to obtain3-hydroxy-4-cyclohexylphenylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the compounds of Example 8, then thecorresponding products are obtained.

EXAMPLE 14 Ethyl 3-methoxy-4-cyclohexylphenylglyoxylate

To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of drydimethylformamide which has been cooled to 0° C. is added dropwise asolution of 0.01 moles of ethyl 3-hydroxy-4-cyclohexylphenylglyoxylatein 10 ml. of dimethylformamide. The reaction mixture is stirred for 15minutes and 0.015 moles of methyliodide is then added dropwise. Themixture is allowed to stir overnight at room temperature. 200 ml. ofwater is added and the resulting mixture is extracted well with ether.The ether extract is washed with water, dried over sodium sulfate,evaporated to dryness and distilled to obtain ethyl3-methoxy-4-cyclohexylphenylglyoxylate.

When ethyl 3-hydroxy-4-cyclohexylphenylglyoxylate in the above exampleis replaced by equimolar amounts of the compounds of Example 13, thenthe corresponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyliodide inthe above reaction, then the product prepared is ethyl3-acetyloxy-4-cyclohexylphenylglyoxylate.

EXAMPLE 15 3-Bromo-4-cyclohexylphenylglyoxylic acid

To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylatesuspension in 225 ml of 40% hydrobromic acid and cooled to 0° C. isadded dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. ofwater. To this mixture is added a solution of 20 g. of cuprous bromidein 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15hours. The reaction mixture is then poured onto ice water, extractedwith chloroform, dried over sodium sulfate and concentrated in vacuo.The residue is then crystallized to obtain3-bromo-4-cyclohexylphenylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by the compounds of Example 8, then the corresponding productsare obtained.

EXAMPLE 16 3-Iodo-4-cyclohexylphenylglyoxylic acid

To 0.05 moles of ethyl 3-amino-4-cyclohexylphenylglyoxylate dissolved ina mixture of 50 g. of ice water and 0.06 moles of concentrated sulfuricacid at 0° C. is added a solution of 0.05 moles of 95% sodium nitrite in8 ml. of water. Stirring is continued for 1/2 hour and then 1.5 ml. ofconcentrated sulfuric acid is added. This solution is poured into an icecold solution of 0.06 moles of potassium iodide in 10 ml. of water. Tothis is added 0.075 g. copper bronze with stirring and the solution iswarmed slowly on a water bath to about 80° C. for 2 hours. After coolingto room temperature the reaction mixture is extracted thrice with 15 ml.portions of chloroform. This is then washed with dilute thiosulfatesolution, water, dried over sodium sulfate and evaporated in vacuo. Theresidue is crystallized to obtain 3-iodo-4-cyclohexylphenylglyoxylicacid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the compounds of Example 8, then thecorresponding products are obtained.

EXAMPLE 17 3-Mercapto-4-cyclohexylphenylglyoxylic acid

To 17.3 g. of ethyl 3-amino-4-cyclohexylphenylglyoxylate in 11.1 ml. ofconcentrated hydrochloric acid and 20 g. of ice is added 4.1 g. ofsodium nitrite in 2 ml. of water. This mixture is stirred for 10 min.and then added gradually to an ice cold solution of 10.3 g. of potassiumethyl xanthate in 14 ml. of water. The reaction is gradually heated over45 minutes to 50° C. and stirred an additional 45 minutes. The mixtureis then cooled, extracted with ether which is then washed with water,dilute sodium hydroxide and water, dried over sodium sulfate andevaporated in vacuo. The residue is dissolved in 35 ml. of boilingethanol to which is added gradually 13 g. of potassium hydroxide. Thereaction is refluxed an additional hour and then evaporated to drynessin vacuo. The residue is dissolved in water and extracted with ether.The alkaline phase is acidified with 6 N sulfuric acid and extractedwith ether. The ether is washed with water, dried over sodium sulfateand evaporated to dryness to obtain3-mercapto-4-cyclohexylphenylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example isreplaced by equimolar amounts of the compounds of Example 8, then thecorresponding products are prepared.

EXAMPLE 18 Ethyl 3-methylthio-4-cyclohexylphenylglyoxylate

To 3.85 g. of ethyl 3-mercapto-4-cyclohexylphenylglyoxylate in 40 ml. ofwater containing 0.65 g. of sodium hydroxide is added 2 ml. of dimethylsulfate with stirring. The reaction mixture is gradually warmed to 40°C. and stirred for 2 hours. The mixture is cooled and extracted withether which is washed with water, dried and evaporated in vacuo. Theresidue is distilled to obtain ethyl3-methylthio-4-cyclohexylphenylglyoxylate.

When the above 3-methylthio-4-cyclohexylphenylglyoxylate is treated with30% H₂ O₂, then the resultant product is ethyl3-methylsulfinyl-4-cyclohexylphenylglyoxylate or ethyl3-methylsulfonyl-4-cyclohexylphenylglyoxylate.

When 3-mercapto-4-cyclohexylphenylglyoxylate in the above example isreplaced by the compounds of Example 17, then the corresponding productsare prepared.

When an equimolar amount of acetyl chloride is used in place of dimethylsulfate in the above reaction, then the product prepared is ethyl3-acetylthio-4-cyclohexylphenylglyoxylate.

EXAMPLE 19 Ethyl 3-chloro-5-trifluoromethyl-4-cyclohexylphenylglyoxylate

To a solution of 0.01 moles of ethyl3-bromo-5-chloro-4-cyclohexylphenylglyoxylate in 50 ml. ofdimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02g. of copper powder. The reaction is shaken in a sealed tube for 5 hoursat 140° C., cooled, filtered and evaporated in vacuo. 200 ml. of wateris added to the residue and extracted with ether. The ether extract isdried, evaporated to dryness and distilled to obtain ethyl3-chloro-5-trifluoromethyl-4-cyclohexylphenylglyoxylate.

EXAMPLE 20 Ethyl 3-amino-5-chloro-4-cyclohexylphenylglyoxylate

A mixture of 17.6 g. (0.05 moles) of ethyl3-chloro-5-nitro-4-cyclohexylphenylglyoxylate in 100 ml. of methanolcontaining 0.05 moles of citric acid and 1.5 g. of 5%palladium-on-carbon is shaken with hydrogen at 3 atm. pressure and 27°C. until 3 moles of hydrogen are absorbed. The mixture is filtered,washed with methanol and the filtrate concentrated in vacuo to obtainethyl 3-amino-5-chloro-4-cyclohexylphenyglyoxylate isolated as thecitrate salt.

EXAMPLE 21 1-(3-Chloro-4-cyclohexylphenyl)-1,2-ethanediol

To lithium aluminum hydride solution (3.9 M; 120 ml) diluted withanhydrous ether (750 ml) is added dropwise 150 g of ethyl3-chloro-4-cyclohexylphenylglyoxylate with stirring, under nitrogen. Themixture is diluted with 250 ml of ether, and is stirred for 2 hours. Thereaction mixture is acidified with 10% hydrochloric acid (450 ml) andextracted with ether/tetrahydrofuran. The aqueous fraction is washedthree times with 50 ml portions of ether. The combined ether fractionsare washed with water until neutral to litmus, and is dried overpotassium carbonate. The ether is removed and the residue is trituratedwith n-hexane, filtered and air-dried to give1-(3-chloro-4-cyclohexylphenyl)-1,2-ethanediol.

When ethyl 3-chloro-4-cyclohexylphenylglyoxylate in the above example isreplaced by the appropriate glyoxylate of Examples 1-20, then thecorresponding product is obtained.

EXAMPLE 22 1-Nitro-4-cyclohexylbenzaldehyde

A mixture of 0.66 moles of 3-nitro-4-cyclohexylphenylglyoxylate isstirred in 1.5 l. of boiling 10% sodium carbonate solution for 16 hours.The mixture is slowly filtered through charcoal into 1.1 l. of ice-cold3 N-hydrochloric acid. The precipitate of crude material is collected ona filter, the recrystallized from benzene to give3-nitro-4-cyclohexylphenylglyoxylic acid.

A mixture of 0.37 moles of 3-nitro-4-cyclohexylphenylglyoxylic acid isstirred under nitrogen in 250 ml. of boiling N,N-dimethylaniline for 16hours. The cooled reaction mixture is poured into 700 ml. of ice-cold 3N-hydrochloric acid and the crude product extracted into hexane. Theproduct is purified by distillation under vacuum to obtain1-nitro-4-cyclohexylbenzaldehyde.

When ethyl 3-nitro-4-cyclohexylphenylglyoxylate in the above example isreplaced by the appropriate glyoxylates of Examples 1-20, then thecorresponding product is obtained.

EXAMPLE 23 3-Chloro-4-cyclohexylbenzaldehyde

To 115 g. of 1-(3-chloro-4-cyclohexylphenyl)-1,2-ethanediol intetrahydrofuran (800 ml.) is added a solution of periodic acid (102 g.)in ether (750 ml.). The reaction mixture is stirred under nitrogenovernight. The reaction mixture is filtered and the filtrate is washedwith water (3×200 ml) and placed over sodium sulfate. Removal of solventgives a liquid residue which is then distilled to give3-chloro-4-cyclohexylbenzaldehyde.

When 1-(3-chloro-4-cyclohexylphenyl)-1,2-ethanediol in the above exampleis replaced by the diols of Example 21, then the corresponding aldehydeis prepared.

EXAMPLE 24 3-Chloro-4-cyclohexylcinnamic Acid

3-Chloro-4-cyclohexylbenzaldehyde (0.1 mole), malonic acid (0.2 moles),and dry pyridine (175 ml) are placed in a 1 l roundbottom flask. Themalonic acid is dissolved by shaking on a steam bath and piperidine (0.5ml) is added. The reaction is allowed to take place on the steam bathfor 4 hours. After standing at room temperature overnight, the mixtureis refluxed for 1 hour and cooled. The reaction mixture is poured into250 ml of ice water and acidified with concentrated hydrochloric acid(80 ml) with stirring. The crystals of product are collected byfiltration, washed with water (4×150 ml) and air dreid.Recrystallization from acetone-water gives 3-chloro-4-cyclohexylcinnamicacid.

When 3-chloro-4-cyclohexylbenzaldehyde in the above example is replacedby the aldehydes of Example 23, then the corresponding cinnamic acid isprepared.

EXAMPLE 25 Ethyl-3-chloro-4-cyclohexylcinnamate

3-Chloro-4-cyclohexylcinnamic acid (20.0 g.; 0.075 moles) is allowed toreflux with 8-10 pieces of Orierite in absolute ethanol (20 ml)containing concentrated sulfuric acid (5 ml) for 21 hours. The cooledreaction mixture is diluted with chloroform and filtered hot. Thefiltrate is washed 3 times with water, once with 10% sodium bicarbonateand twice more with water. After drying over sodium sulfate, the solventis removed to give ethyl 3-chloro-4-cyclohexylcinnamate.

When 3-chloro-4-cyclohexylcinnamic acid in the above example is replacedby the cinnamic acids of Example 24, then the corresponding cinnamate isprepared.

EXAMPLE 26 Ethyl α,β-Dibromo-β-(3-chloro-4-cyclohexylphenyl)propionate

A cold solution of ethyl 3-chloro-4-cyclohexylcinnamate (0.075 moles) inchloroform (47 ml) is brominated by the portion-wise addition of bromine(4.1 ml; 10% excess) in chloroform (10 ml) with shaking and stirring.The solution is allowed to stand at room temperature for 11/4 hours andthe solvent is removed to give ethylα,β-dibromo-β-(3-chloro-4-cyclohexylphenyl)propionate.

When ethyl 3-chloro-4-cyclohexylcinnamate in the above example isreplaced by the cinnamates of Example 25, then the correspondingα,β-dibromopropionate is prepared.

EXAMPLE 27 3-Chloro-4-cyclohexylpropiolic Acid

Powdered ethyl α,β-dibromo-β-(3-chloro-4-cyclohexyl)propionate (33.0 g.)is added portion-wise to 20% ethanolic potassium hydroxide (135 ml) atroom temperature. The mixture is refluxed on a steam bath for 6 hours.The alcohol is evaporated and the residue is dissolved in water andcovered with ether and is acidified with cold, dilute hydrochloric acid.The ether layer is washed with water, saline, and dried over sodiumsulfate. The ether is removed to give a residue which is triturated withcarbon tetrachloride. Recrystallization is carried out from aceticacid-water. This material is digested and triturated with boiling carbontetrachloride to give 3-chloro-4-cyclohexylpropiolic acid.

When α,β-dibromo-β-(3-chloro-4-cyclohexyl)propionate in the aboveexample is replaced by the α,β-dibromopropionate of Example 26, then thecorresponding propiolic acid is prepared.

EXAMPLE 28 3-Chloro-4-cyclohexylethynylbenzene

3-chloro-4-cyclohexylphenylpropiolic acid (7.3 g.) is heated at120°-124° for 5 hours in quinoline. The reaction product is diluted withwater and washed thoroughly with dilute hydrochloric acid. This isfollowed by washing with sodium bicarbonate (10%). The material ispassed through a short aluminum (H⁺) column, eluted with N-hexane togive a fraction free of carbonyl absorption (I.R.). Removal of solventgives 3-chloro-4-cyclohexylethynylbenzene.

When 3-chloro-4-cyclohexylphenylpropiolic acid in the above example isreplaced by the propiolic acids of Example 27, then the correspondingacetylene is prepared.

EXAMPLE 29 3-Chloro-4-cyclohexylethynylbenzene

3-Chloro-4-cyclohexylacetophenone (0.25 moles) and phosphoruspentachloride (0.31 moles) are placed in a 3-necked flask equipped witha mechanical stirrer, a condenser connected to a nitrogen inlet, and athermometer. The mixture is stirred at 33°-35° C. for 3 days. The cooledreaction mixture is poured onto 800 g. of ice and extracted with 3×500ml. of ether. The ether fraction is washed with 2×100 ml water 4×100 mlof 5% sodium hydroxide, 3×50 ml water, 2×50 ml of saturated saline anddried over sodium sulfate. The ether is removed to give the chlorinatedintermediate. The intermediate is dissolved in anhydrous THF (200 ml)and is added dropwise to a freshly prepared solution of sodamide inliquid ammonia, using a dry-ice condenser. The reaction mixture isallowed to stir at room temperature overnight; then, it is poured into50 ml of water and 500 ml of ether. The ether fraction is washed with3×50 ml water and 50 ml of saturated saline and is dried over sodiumsulfate. Removal of solvent gives a residue which is distilled to give3-chloro-4-cyclohexylethynylbenzene.

EXAMPLE 30

When the procedures of Example 1-29 are followed, the compounds belowmay be prepared.

p-cyclopentylethynylbenzene

p-cyclohexylethynylbenzene

p-cycloheptylethynylbenzene

3-bromo-4-cyclohexylethynylbenzene

3-fluoro-4-cyclohexylethynylbenzene

3-iodo-4-cyclhexylethynylbenzene

3-nitro-4-cyclohexylethynylbenzene

3-trifluoromethyl-4-cyclohexylethynylbenzene

3-amino-4-cyclohexylethynylbenzene

3-methylamino-4-cyclohexylethynylbenzene

3-acetylamino-4-cyclohexylethynylbenzene

3-dimethylamino-4-cyclohexylethynylbenzene

3-cyano-4-cyclohexylethynylbenzene

3-hydroxy-4-cyclohexylethynylbenzene

3-methoxy-4-cyclohexylethynylbenzene

3-acetyloxy-4-cyclohexylethynylbenzene

3-mercapto-4-cyclohexylethynylbenzene

3-methylthio-4-cyclohexylethynylbenzene

3-methylsulfinyl-4-cyclohexylethynylbenzene

3-methylsulfonyl-4-cyclohexylethynylbenzene

3-acetylthio-4-cyclohexylethynylbenzene

3,5-dichloro-4-cyclohexylethynylbenzene

3-chloro-5-trifluoromethyl-4-cyclohexylethynylbenzene

3,5-dinitro-4-cyclohexylethynylbenzene

3-chloro-5-nitro-4-cyclohexylethynylbenzene

3-chloro-5-amino-4-cyclohexylethynylbenzene

3-chloro-5-bromo-4-cyclohexylethynylbenzene

3-chloro-5-fluoro-4-cyclohexylethynylbenzene

3-chloro-4-cyclopentylethynylbenzene

3-bromo-4-cyclopentylethynylbenzene

3-fluoro-4-cyclopentylethynylbenzene

3-trifluoromethyl-4-cyclopentylethynylbenzene

3-nitro-4-cyclopentylethynylbenzene

3-cyano-4-cyclopentylethynylbenzene

3-methylsulfonyl-4-cyclopentylethynylbenzene

3,5-dichloro-4-cyclopentylethynylbenzene

3-chloro-5-nitro-4-cyclopentylethynylbenzene

3-chloro-4-cycloheptylethynylbenzene

3-bromo-4-cycloheptylethynylbenzene

3-fluoro-4-cycloheptylethynylbenzene

3-trifluoromethyl-4-cycloheptylethynylbenzene

3-nitro-4-cycloheptylethynylbenzene

3-cyano-4-cycloheptylethynylbenzene

3-methylsulfonyl-4-cycloheptylethynylbenzene

3,5-dichloro-4-cycloheptylethynylbenzene

3-chloro-5-nitro-4-cycloheptylethynylbenzene

p-isopropylethynylbenzene

p-isobutylethynylbenzene

3-chloro-4-methylethynylbenzene

3-chloro-4-ethylethynylbenzene

3-chloro-4-propylethynylbenzene

3-chloro-4-i-propylethynylbenzene

3-chloro-4-butylethynylbenzene

3-chloro-4-i-butylethynylbenzene

3-chloro-4-sec-butylethynylbenzene

3-chloro-4-t-butylethynylbenzene 3-chloro-4-pentylethynylbenzene

3-chloro-4-hexylethynylbenzene

3-chloro-4-heptylethynylbenzene

3-nitro-4-i-propylethynylbenzene

3-nitro-4-i-butylethynylbenzene

3-bromo-4-i-butylethynylbenzene

3-fluoro-4-i-butylethynylbenzene

3-cyano-i-butylethynylbenzene

3-methylsulfonyl-4-i-butylethynylbenzene

3-trifluoromethyl-4-i-butylethynylbenzene

2'-chloro-4-ethynylbiphenyl

2'-fluoro-4-ethynylbiphenyl

2'-bromo-4-ethynylbiphenyl

2'-nitro-4-ethynylbiphenyl

I claim:
 1. A method of treating inflammation, pain or fever in awarm-blooded animal which comprises administering to the animal aneffective non-toxic amount of an active agent which is a compound of theformula ##STR8## where R is hydrogen,alkyl of 1 to 7 carbon atoms,cycloalkyl of 5 to 7 carbon atoms, 1to 7 carbon atoms substitutedcycloalkyl of 5 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms,phenyl or substituted phenyl where the substituent is Y"; Y and Y' areeach selected from the group consisting of hydrogen and lower alkoxy of1 to 7 carbon atoms; Y" is selected from the group consisting of Y,lower alkyl of 1 to 7 carbon atoms and trifluoromethyl,with the provisothat at least one of Y and Y' is other than hydrogen.
 2. Apharmaceutical preparation in dosage unit form adapted foradministration to warm blooded animals for relief from inflammation,pain or fever, comprising, per dosage unit, an effective non-toxicamount of an active compound of the formula ##STR9## where R ishydrogen, alkyl of 1 to 7 carbon atoms,cycloalkyl of 5 to 7 carbonatoms, 1 to 7 carbon atoms substituted cycloalkyl of 5 to 7 carbonatoms, cycloalkenyl of 5 to 7 carbon atoms, phenyl or substituted phenylwhere the substituent is Y"; Y and Y' are each selected from the groupconsisting of hydrogen and lower alkoxy of 1 to 7 carbon atoms, Y" isselected from the group consisting of Y, lower alkyl of 1 to 7 carbonatoms, and trifluoromethyl,with the proviso that at least one of Y andY' is other than hydrogen, and a suitable pharmaceutically acceptablecarrier.
 3. A pharmaceutical preparation adapted for administration towarm blooded animals, comprising an effective amount of an activecompound of the formula: ##STR10## where R is hydrogen, alkyl of 1 to 7carbon atoms,cycloalkyl of 5 to 7 carbon atoms, 1to 7 carbon atoms alkylsubstituted cycloalkyl of 5 to 7 carbon atoms, cycloalkenyl of 5 to 7carbon atoms, phenyl, or substituted phenyl where the substituent is Y";Y and Y' are each selected from the group consisting of hydrogen andlower alkoxy of 1 to 7 carbon atoms; Y" is selected from the groupconsisting of Y, lower alkyl of 1 to 7 carbon atoms, andtrifluoromethylwith the proviso that at least one of Y and Y' is otherthan hydrogen, and a suitable pharmaceutically acceptable carrier.
 4. Apreparation according to claim 3, wherein the active compound is3-methoxy-4-cyclohexylethynylbenzene.
 5. A preparation according toclaim 3, wherein the active compound is 2'-methoxy-4-ethynylbiphenyl. 6.A preparation according to claim 3, wherein the active compound is3'-methoxy-4-ethynylbiphenyl.
 7. A preparation according to claim 3,wherein the active compound is 2'-methoxy-4'-n-butyl-4-ethynylbiphenyl.8. A preparation according to claim 3, wherein the active compound is(2-methyl-4-n-butoxyphenyl) acetylene.